**6. Treatment options**

more prevalent in older patients. In patients with a history of head and neck cancer and exposure to radiation therapy, intimal hyperplasia and other radiation changes would be the most likely underlying cause of the stenosis, and are typically more difficult to treat compared with atherosclerotic lesions [13]. Patients involved in a recent trauma or neck manipulation may have an arterial dissection that can lead to significant arterial stenosis or occlusion [14]. All of these causes could present with or without symptoms, and although the likelihood of symptoms may be more prevalent in higher degrees of stenosis, it is important to correlate the clinical history and presentation with the radiographic findings when evaluating carotid stenosis, as this will help to drive the decisions for conservative or invasive treatment of lesions identified. Currently, the US Preventive Services Task Force recommends against screening

Several clinical trials have been performed to evaluate the patient populations who will benefit from various treatment options, including medical management, surgical intervention with carotid endarterectomy (CEA) or carotid angioplasty with or without stent placement (CAS), and also with or without distal embolic protection devices for endovascular treatments.

One publication from the Netherlands reviewed four major population based studies for a meta-analysis to determine the prevalence of moderate (50-70%) and severe (>70%) carotid stenosis in men and women at various ages [16]. The investigators determined that the prevalence of asymptomatic moderate carotid stenosis ranged from 0.2% (95% CI, 0.0% to 0.4%) in men aged <50 years to 7.5% (5.2% to 10.5%) in men aged ≥80 years, and severe carotid stenosis ranged from 0.1% (0.0% to 0.3%) in men aged <50 years to 3.1% (1.7% to 5.3%) in men aged ≥80 years. For women, the prevalence of asymptomatic moderate carotid stenosis ranged from 0% (0% to 0.2%) in those aged<50 years to 5.0% (3.1% to 7.5%) in women aged ≥80 years, while severe asymptomatic carotid stenosis for women ranged from 0% (0.0% to 0.2%) to 0.9% (0.3% to 2.4%), between these age groups. Although this data helps to understand the preva‐ lence of this condition, it can only be applied to this particular population that was studied.

Traditionally, patients who presented with stroke or TIA symptoms would undergo diagnostic catheter angiography for the diagnosis of carotid stenosis. With the advent of current noninvasive vascular imaging since the 1980's such as carotid duplex ultrasound, MRA and CTA, the most common presentation of carotid stenosis is an incidental finding of asymptomatic stenosis noted on one of these imaging studies which could be performed for a variety of reasons other than for stroke or TIA, including screening imaging studies performed to follow up clinical exam findings such as auscultation of a carotid bruit. The sensitivity and specificity of auscultation of a carotid bruit when used to evaluate for carotid stenosis are extremely poor. One study compared the sensitivity and specificity of detecting carotid or vertebral stenosis with duplex ultrasound evaluation compared with the gold standard catheter angiogram and also reviewed the presence or absence of a cervical bruit on examination. This study showed that the location and estimated degree of stenosis was accurately identified in 97% of carotid and 90% of vertebral stenosis cases with duplex ultrasound compared with catheter angiog‐ raphy, but the presence of a bruit on exam would only correctly diagnose 27.6% of patients with confirmed hemodynamically significant stenosis, and was falsely positive in 22.6% of

for carotid stenosis in the general asymptomatic population [15].

208 Carotid Artery Disease - From Bench to Bedside and Beyond

The medical management of carotid stenosis has revolved around anti-inflammatory and antiplatelet agents as the drugs of choice. Marquardt et al studied the UK population and docu‐ mented the frequency of ipsilateral ischemic stroke in the setting of asymptomatic carotid stenosis ≥50% [20]. It was reported that with adequate medical management, the risk was 0.34% for any ipsilateral non-disabling stroke, 0.0% for severe disabling stroke, and 1.78% for ipsilateral TIA. These results would support best medical management for all asymptomatic carotid stenosis, irrespective of the degree of stenosis. Aspirin is known to have anti-inflam‐ matory properties by irreversible blockade of the cyclooxygenase (COX)-1 and COX-2 pathways of arachidonic acid metabolism. Carotid fibrous plaque formation and remodeling are influenced by several factors including MMPs secreted by leukocytes in the intima which remodel the extracellular matrix, and this results in thrombosis with vulnerable plaques in which the fibrous cap has become significantly thinned and embolic events resulting in TIA and stroke may ensue [1]. The Clopidogrel and Aspirin for the Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial evaluated the use of aspirin alone vs aspirin with clopidogrel in symptomatic carotid stenosis >50% and found that combination therapy reduced the frequency of asymptomatic microembolization as detected by transcranial doppler ultrasound more effectively than aspirin alone [21].

Several major trials evaluating asymptomatic carotid stenosis include the Veterans Adminis‐ tration Trial (VA, 1993 [22]), the Asymptomatic Carotid Surgery Trial (ACST, 1994 [23]) and the Asymptomatic Carotid Artery Stenosis Trial (ACAS, 1995 [24]). The VA trial looked at medical management alone with aspirin 650mg po BID versus combined medical management with the same aspirin dose and with CEA for asymptomatic carotid stenosis of 50% or greater in 444 men in the VA medical system. This study failed to show any statistically significant differences in clinical outcome between these two groups [22]. The ACST group evaluated the timing of CEA for patients with asymptomatic carotid stenosis of 60% or greater. Patients were treated with best medical management and the treatment group received CEA as soon as possible. The second group only received CEA if symptoms developed while on medical therapy. A total of 3120 patients were enrolled and this study failed to show any statistically significant differences in long term clinical outcome between groups [23]. In 1995, the ACAS trial was published which reviewed the results of 1662 asymptomatic patients with >60% carotid stenosis. Patients were randomized into two groups, the first consisting of medical therapy alone with aspirin 325mg daily and the second group treated with medical therapy and CEA within 2 weeks of randomization [24]. This trial found a reduced 5-year stroke risk from 11.0% in the medical arm to 5.1% in the surgical arm with a 3% perioperative morbidity and mortality.

have been examined and in a report from Skelly et al, these risk factors include prior stroke,

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Large trials designed to evaluate surgical versus medical treatment for symptomatic carotid stenosis include the Veterans Administration 309 Trial (VA309, 1991 [36]), the European Carotid Surgery Trial (ECST, 1998 [37]), and the North American Symptomatic Carotid Endarterectomy Trial (NASCET, 1998 [26]). VA309 evaluated the results of treating 189 symptomatic patients with >50% carotid stenosis ipsilateral to the symptoms with best medical management or a combined approach of best medical management with CEA. The study found a statistically significant reduction in the stroke risk over 11.9 months for the surgical arm compared to the medical arm (7.7% vs 19.4%, P=0.11) [36]. In 1998, both ECST and NASCET were published. ECST evaluated 3024 patients with some degree of symptomatic carotid stenosis that was determined by varying modality and varying quality vascular imaging studies. The trial randomized 1811 patients to the surgical arm and 1213 patients to the medical arm, and the overall risk of surgery was determined to be about 7%, which did not vary with the degree of stenosis. For symptomatic carotid stenosis (as measured by the ECST method) of greater than 80%, the three-year major stroke or death rate was 14.9% for the surgical arm and 26.5% in the medical arm, revealing a statistically significant benefit for surgery in that group [37]. NASCET evaluated 1108 patients with symptomatic carotid stenosis in the CEA arm and 1118 demographically similar patients in the best medical management arm. The results showed no benefit for surgery below 50% stenosis, some benefit particularly in men with moderate stenosis (50-69%) and clear benefit for surgery with severe stenosis (>70%). The rate of any ipsilateral stroke over five-year follow up for moderate carotid stenosis (50-69%) was 15.7% in the surgical arm and 22.2% in the medical arm (P=0.045), with the immediate

The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) evaluated 2502 symptomatic and asymptomatic carotid stenosis patients who were randomly assigned to CEA or CAS [38]. The study found no significant differences in combined stroke, myocardial infarction and death risk over 4 year follow up between these groups, however, there was a trend toward more myocardial infarctions in the surgical arm (6.8% vs 7.2%, CAS vs CEA, P=0.51) and a statistically significant higher rate of periprocedural stroke in the endovascular arm (6.4% vs 4.7%, CAS vs CEA, P=0.03). A study published in February 2013 evaluated the effect of these perioperative complications on long term survival. According to this trial, having a stroke within the first year resulted in a two-fold lower survival rate (HR=6.6; CI=3.7-12) than those patients who suffered a perioperative myocardial infarction two years after intervention (HR=3.6;CI=2-6.8), but this difference becomes negligible at 5 years (HR=2.7;

The Carotid and Vertebral Transluminal Angioplasty Study (CAVATAS) examined the treatment of carotid stenosis with carotid endarterectomy (N=213) vs endovascular treatment with angioplasty alone (N=145) or angioplasty and stent placement (N=50). The rate of recurrent stenosis >70% after endovascular therapy for all patients treated with or without stent placement was about 3 times higher than the restenosis rate after endarterectomy after 5 years of follow up (30.7% vs 10.5%, p=<0.0001). However, of the endovascular treated patients,

transient ischemic attack, amaurosis fugax, and prior neck cancer [35].

perioperative stroke or death risk being reported as 2% [26].

CI=1.7-4.3 vs HR=2.8; CI=1.8-4.3) [39].

Catheter based diagnostic cerebral angiography remains the gold standard imaging modality for diagnosing and measuring carotid stenosis. The risk of stroke for asymptomatic patients is 2-3% annually and 12% in symptomatic stroke patients [20,25]. Clinical trials have demon‐ strated measurable differences in the treatment strategy for symptomatic versus asymptomatic carotid stenosis. A majority of data advocates best medical management for asymptomatic carotid stenosis because of the very low incidence of ipsilateral stroke, regardless of the degree of stenosis. According to the ACAS and NASCET trial results, revascularization is recom‐ mended for symptomatic male patients with ≥50% ipsilateral cervical internal carotid artery stenosis, while revascularization is not recommended for symptomatic female patients until the severity of ipsilateral cervical carotid stenosis reaches ≥70% [26], however, this difference between men and women has remained somewhat controversial and these results have not been consistently reproduced [27]. Currently, carotid endarterectomy continues to be the gold standard for revascularization. If the patient has significant risk factors placing them at a high risk for endarterectomy, then revascularization via carotid angioplasty and stenting is an alternative therapy. Such risk factors typically include: previous ipsilateral carotid endarter‐ ectomy, recent myocardial infarction within previous thirty days, contralateral carotid occlusion, radiation to the neck, chronic obstructive pulmonary disease, and previous carotid stent.

Carotid stent placement is offered to patients who have no contraindications to long-term antiplatelet agent use and who are at a high risk for surgery. Distal embolic protection devices are generally used to lower the risk of embolic events from stent placement and balloon angio‐ plasty, but recent recommendations vary; cases where there is a reasonably high potential for distal embolic events during the angioplasty procedure may benefit from distal protection devices [28–32]. Carotid angioplasty alone without stent placement is associated with a very high rate of re-stenosis. The CAVATAS trial examined the treatment of carotid stenosis with angioplasty alone (N=145) versus carotid angioplasty and stent placement (N=50) vs carotid endarterectomy (N=213). This trial showed that carotid endarterectomy resulted in signifi‐ cantly lower rates of carotid re-stenosis >70% 5 years after treatment compared with endovas‐ cular therapy (30.7% vs 10.5%). Additionally, in the endovascular treatment group, the patients treated with angioplasty alone had a higher rate of re-stenosis >70% compared with those treated with stent placement (36.2% vs 16.6%) [33]. With the placement of a stent, the in-stent re-stenosis rate has been reported to be as low as 5% after four years [34]. Risk factors that may increase the likelihood of recurrent stenosis after carotid angioplasty, stent or endarterectomy have been examined and in a report from Skelly et al, these risk factors include prior stroke, transient ischemic attack, amaurosis fugax, and prior neck cancer [35].

possible. The second group only received CEA if symptoms developed while on medical therapy. A total of 3120 patients were enrolled and this study failed to show any statistically significant differences in long term clinical outcome between groups [23]. In 1995, the ACAS trial was published which reviewed the results of 1662 asymptomatic patients with >60% carotid stenosis. Patients were randomized into two groups, the first consisting of medical therapy alone with aspirin 325mg daily and the second group treated with medical therapy and CEA within 2 weeks of randomization [24]. This trial found a reduced 5-year stroke risk from 11.0% in the medical arm to 5.1% in the surgical arm with a 3% perioperative morbidity

Catheter based diagnostic cerebral angiography remains the gold standard imaging modality for diagnosing and measuring carotid stenosis. The risk of stroke for asymptomatic patients is 2-3% annually and 12% in symptomatic stroke patients [20,25]. Clinical trials have demon‐ strated measurable differences in the treatment strategy for symptomatic versus asymptomatic carotid stenosis. A majority of data advocates best medical management for asymptomatic carotid stenosis because of the very low incidence of ipsilateral stroke, regardless of the degree of stenosis. According to the ACAS and NASCET trial results, revascularization is recom‐ mended for symptomatic male patients with ≥50% ipsilateral cervical internal carotid artery stenosis, while revascularization is not recommended for symptomatic female patients until the severity of ipsilateral cervical carotid stenosis reaches ≥70% [26], however, this difference between men and women has remained somewhat controversial and these results have not been consistently reproduced [27]. Currently, carotid endarterectomy continues to be the gold standard for revascularization. If the patient has significant risk factors placing them at a high risk for endarterectomy, then revascularization via carotid angioplasty and stenting is an alternative therapy. Such risk factors typically include: previous ipsilateral carotid endarter‐ ectomy, recent myocardial infarction within previous thirty days, contralateral carotid occlusion, radiation to the neck, chronic obstructive pulmonary disease, and previous carotid

Carotid stent placement is offered to patients who have no contraindications to long-term antiplatelet agent use and who are at a high risk for surgery. Distal embolic protection devices are generally used to lower the risk of embolic events from stent placement and balloon angio‐ plasty, but recent recommendations vary; cases where there is a reasonably high potential for distal embolic events during the angioplasty procedure may benefit from distal protection devices [28–32]. Carotid angioplasty alone without stent placement is associated with a very high rate of re-stenosis. The CAVATAS trial examined the treatment of carotid stenosis with angioplasty alone (N=145) versus carotid angioplasty and stent placement (N=50) vs carotid endarterectomy (N=213). This trial showed that carotid endarterectomy resulted in signifi‐ cantly lower rates of carotid re-stenosis >70% 5 years after treatment compared with endovas‐ cular therapy (30.7% vs 10.5%). Additionally, in the endovascular treatment group, the patients treated with angioplasty alone had a higher rate of re-stenosis >70% compared with those treated with stent placement (36.2% vs 16.6%) [33]. With the placement of a stent, the in-stent re-stenosis rate has been reported to be as low as 5% after four years [34]. Risk factors that may increase the likelihood of recurrent stenosis after carotid angioplasty, stent or endarterectomy

and mortality.

210 Carotid Artery Disease - From Bench to Bedside and Beyond

stent.

Large trials designed to evaluate surgical versus medical treatment for symptomatic carotid stenosis include the Veterans Administration 309 Trial (VA309, 1991 [36]), the European Carotid Surgery Trial (ECST, 1998 [37]), and the North American Symptomatic Carotid Endarterectomy Trial (NASCET, 1998 [26]). VA309 evaluated the results of treating 189 symptomatic patients with >50% carotid stenosis ipsilateral to the symptoms with best medical management or a combined approach of best medical management with CEA. The study found a statistically significant reduction in the stroke risk over 11.9 months for the surgical arm compared to the medical arm (7.7% vs 19.4%, P=0.11) [36]. In 1998, both ECST and NASCET were published. ECST evaluated 3024 patients with some degree of symptomatic carotid stenosis that was determined by varying modality and varying quality vascular imaging studies. The trial randomized 1811 patients to the surgical arm and 1213 patients to the medical arm, and the overall risk of surgery was determined to be about 7%, which did not vary with the degree of stenosis. For symptomatic carotid stenosis (as measured by the ECST method) of greater than 80%, the three-year major stroke or death rate was 14.9% for the surgical arm and 26.5% in the medical arm, revealing a statistically significant benefit for surgery in that group [37]. NASCET evaluated 1108 patients with symptomatic carotid stenosis in the CEA arm and 1118 demographically similar patients in the best medical management arm. The results showed no benefit for surgery below 50% stenosis, some benefit particularly in men with moderate stenosis (50-69%) and clear benefit for surgery with severe stenosis (>70%). The rate of any ipsilateral stroke over five-year follow up for moderate carotid stenosis (50-69%) was 15.7% in the surgical arm and 22.2% in the medical arm (P=0.045), with the immediate perioperative stroke or death risk being reported as 2% [26].

The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) evaluated 2502 symptomatic and asymptomatic carotid stenosis patients who were randomly assigned to CEA or CAS [38]. The study found no significant differences in combined stroke, myocardial infarction and death risk over 4 year follow up between these groups, however, there was a trend toward more myocardial infarctions in the surgical arm (6.8% vs 7.2%, CAS vs CEA, P=0.51) and a statistically significant higher rate of periprocedural stroke in the endovascular arm (6.4% vs 4.7%, CAS vs CEA, P=0.03). A study published in February 2013 evaluated the effect of these perioperative complications on long term survival. According to this trial, having a stroke within the first year resulted in a two-fold lower survival rate (HR=6.6; CI=3.7-12) than those patients who suffered a perioperative myocardial infarction two years after intervention (HR=3.6;CI=2-6.8), but this difference becomes negligible at 5 years (HR=2.7; CI=1.7-4.3 vs HR=2.8; CI=1.8-4.3) [39].

The Carotid and Vertebral Transluminal Angioplasty Study (CAVATAS) examined the treatment of carotid stenosis with carotid endarterectomy (N=213) vs endovascular treatment with angioplasty alone (N=145) or angioplasty and stent placement (N=50). The rate of recurrent stenosis >70% after endovascular therapy for all patients treated with or without stent placement was about 3 times higher than the restenosis rate after endarterectomy after 5 years of follow up (30.7% vs 10.5%, p=<0.0001). However, of the endovascular treated patients, the occurrence of restenosis >70% in the angioplasty alone group compared to the stent group was more than twice as frequent (36.2% vs 16.6%, p=0.04). Of all patients with >70% restenosis in the first year after treatment with CEA or CAS compared to the patients with <70% restenosis in this same time period, there was a trend toward a higher ipsilateral stroke rate in the greater stenosis group, but this result did not reach clinical significance (9.7% vs 5.4%, p=0.4) [33]. These results suggest that CEA provides the greatest durability of treatment with fewer cases of hemodynamically significant recurrent stenosis compared with stent placement, although stent placement is significantly superior to angioplasty alone for long-term durability. Treated patients should be followed for recurrent stenosis, and although the greater stenosis group did not have a statistically significant increase in the number of ipsilateral stroke events, it would be wise to more closely monitor these patients, be more aggressive with medical management with anti-platelet agents, or even offer repeat treatment for those patients with progressively worsening stenosis during the follow up period.

drain is often recommended in selected cases, particularly if the patient is taking both aspirin and clopidogrel at the time of the surgery, and if it is difficult to maintain a dry surgical field

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The approach to the carotid sheath for the CEA begins with positioning the patient in the supine position on the operating table with the head turned slightly toward the contralateral side and the neck slightly extended for optimum exposure. The planned incision line should be marked with a skin marker along the anterior border of the sternocleidomastoid muscle, which would be approximately parallel to the expected course of the carotid artery, for optimum exposure. The neck should be prepped behind and below the ear from just above the mastoid down to the upper chest, just below the clavicle, and from midline out laterally to the anterolateral border of the trapezius muscle above the shoulder. After proper sterile technique for preparation and draping of the operative field, the skin is incised along the previously marked incision site. The platysma muscle is encountered and split parallel to the muscle fibers, which is also parallel to the incision. The omohyoid muscle is separated as needed for adequate exposure of the common carotid artery (CCA) and at least 2-3cm of the ECA and internal carotid artery (ICA). If additional exposure is required superiorly, the superior aspect of the planned incision should be extended superiorly and posteriorly just below the mastoid, and care should be taken to not injure the hypoglossal nerve at this level during the deeper dissection. Care should be taken to avoid injury to the recurrent laryngeal nerve or the esophagus during the dissection to the carotid sheath. The carotid artery typically resides medially in the carotid sheath, the internal jugular vein typically lies lateral to the carotid artery, and the vagus nerve typically lies deep to both of these structures and between

The systolic blood pressure (SBP) is raised prior to placing the clamp, typically to 140-160 mmHg for patients who are normotensive at baseline, to help promote perfusion through collateral circulation. Generally, raising the SBP by about 20% of the baseline should allow for adequate collateral circulation. The carotid artery is then clamped in the following order when the surgeon is ready to perform the endarterectomy, with the ICA being clamped first followed by the CCA (typically with a Fogarty carotid clamp or other atraumatic clamp device), followed by the ECA. If neuromonitoring is used, these signals are also monitored continuously, and changes in the SSEP and or MEP signals that would be consistent with ischemia changes should

The arteriotomy is performed with a #11 scalpel blade until a pair of Potts scissors can be inserted into the true lumen and the incision can be extended from the CCA to the ICA full thickness through the plaque. Care must be taken to identify the superior thyroid artery origin, especially if there is back-bleeding after performing the arteriotomy, as this may arise very near the carotid bifurcation, unless a temporary clip is applied to this arterial branch. The plaque is then carefully but quickly teased from the endothelial layer of the carotid artery and the plaque is transected as far as possible with the exposure and the carotid artery wall is inspected for loose debris which is carefully removed and irrigated with heparinized saline. The carotid artery is then sutured with 6-0 prolene in simple running fashion, using a minimal full thickness stitch to reapproximate the incised vessel edges without causing additional

prompt the surgeon to selectively place a shunt into that carotid artery.

at the time of the operation.

them.
